Summary

The purpose of this study is to evaluate the safety and effectiveness of an investigational
study drug called carfilzomib. The investigators want to find out what effects, good and/or
bad, it has on patients and their cancer if treatment continues beyond previous carfilzomib
treatment study.

Carfilzomib (KyprolisTM) is approved by the U.S. Food and Drug Administration (FDA) to be
used only in certain U.S. patients with relapsed and refractory multiple myeloma that have
tried and failed other therapies. It has not been approved to be used for any other disease
or condition.

In this study, carfilzomib is referred to as an investigational study drug because it is not
approved for use in all patients with multiple myeloma in the United States, and it is not
approved by some regulatory authorities (the agencies that are responsible for approving the
use of a medicine in a country such as Health Canada).

Carfilzomib is a type of drug called a proteasome inhibitor. A proteasome is a protein
found within cells that has the important role of identifying and marking damaged proteins
that are needed to be destroyed by the cell for survival. The inhibition of the proteasome
allows for damaged protein to accumulate within cells. This accumulation of damaged protein
causes the cell to die.

Study Design

Carfilzomib 20 mg/m2 on day 1, 2 then 56 mg/m2 days 8, 9 and 15, 16 over 30 minutes every 28 days. Dexamethasone 4 mg (8 mg if > 45 mg/m2) orally each day of carfilzomib therapy. If less than a partial remission (PR) after 4 cycles, add rituximab 375 mg/m2 on day 16 of each cycle. Patients who meet the criteria for progression prior to 4 cycles of therapy will have rituximab added to their treatment. For patients receiving rituximab, the carfilzomib dose will be decreased to 27 mg/m2. Patients will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.

carfilzomib
Kyprolis

If you decide to participate in the study, you will receive carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days for a minimum of 2 cycles (approximately 2 months). You may receive additional cycles for as long as your disease remains stable or improved or until your study doctor determines that you should stop receiving the study drug or you decide to stop participating in the study.

rituximab
Rituxan

If you decide to participate in the study, in addition to the carfilzomib and possible dexamethasone administration, If less than a partial remission (PR) after 4 cycles is achieved, rituximab 375 mg/m2 on day 16 of each subsequent cycle will be added to the treatment. Subjects who meet the criteria for progression prior to 4 cycles of therapy will have rituximab 375 mg/m2 weekly for 4 consecutive weeks every 3 cycles added to the treatment. Subjects will be treated to maximal response plus 2 additional cycles to a maximum of 12 cycles.
At the beginning of every cycle, your study doctor will see if your general health is satisfactory. You will be asked to report any side effects or problems you have had since the start of the last treatment cycle as well as any medication change(s).

dexamethasone

If you decide to participate in the study, you will receive carfilzomib on Days 1, 2, 8, 9, 15, and 16 every 28 days for a minimum of 2 cycles (approximately 2 months). You may receive additional cycles for as long as your disease remains stable or improved or until your study doctor determines that you should stop receiving the study drug or you decide to stop participating in the study.
You will also receive dexamethasone weekly on Days 1, 2, 8, 9, 15 and 16 starting with cycle 1 and continuing every cycle thereafter.

Primary Outcomes

time frame:
Participants will be evaluated every 28 days (1 cycle) until progression or a maximum of 12 cycles

Secondary Outcomes

Measure

Determine the tolerability by assessing drug toxicity in patients with WM

time frame:
On days 1, 2, 8, 9, 15 and 16 of each 28 day cycle

Determine duration of response in patients with WM.

time frame:
Participants will be assessed for duration of response at the end of each 28 day cycle

Determine time to progression

time frame:
From date of first carfilzomib dose to date of documented progression or start of alternative therapy whichever came first up to a period of 24 months

Determine progression free survival

time frame:
Participants will be assessed for progression free survival at the end of a 28 day cycle

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria:
- Biopsy proven WM with relapsed/refractory symptomatic disease are eligible for
enrollment.
- Bone marrow lymphoplasmacytosis with:
- > 10% lymphoplasmacytic cells (measured within 28 days prior to registration OR
- Aggregates or sheets of one of the following: lymphocytes, plasma cells or
lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior
to registration).
- Measurable disease defined as a quantitative IgM monoclonal protein of >500
mg/dL obtained within 28 days prior to registration
- CD20+ bone marrow or lymph node by immunohistochemistry or flow cytometry
obtained within 28 days prior to registration
- Lymph node biopsy must be done <28 days prior to registration if used as an
eligibility criterion for study entry.
- Symptomatic disease, as defined by the IWWM, includes the following criteria:
Hemoglobin less than 10 g/dL, platelet count less than 100,000 uL, bulky adenopathy
or organomegaly, symptomatic hyperviscosity syndrome, severe neuropathy, amyloidosis,
cryoglobulinemia, cold agglutinin disease, or evidence of transformation high-grade
non-Hodgkin's lymphoma.
- Patients must not be receiving concurrent steroids > 10 mg prednisone (or equivalent)
per day.
- Prior irradiation is allowed if > 28 days prior to registration have elapsed since
the date of last treatment.
- Women must not be pregnant or breast-feeding due to the fact that the reproductive
risk to humans taking carfilzomib is unknown. All females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule
out pregnancy. A female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months).
- Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception throughout the study and for 8 weeks after
completion of the study.
- Patients must be > 18 years old.
- Patients must have ECOG performance status of < 2.
- Patients may have received prior bortezomib therapy.
- Adequate hepatic function, with serum ALT ≤ 3times the upper limit of normal and
serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization
- Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization
- Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be
receiving red blood cell [RBC] transfusions in accordance with institutional
guidelines)
- Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if WM involvement in the bone marrow is >
50%) within 14 days prior to randomization
- Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization,
either measured or calculated using a standard formula (e.g., Cockcroft and Gault)
Exclusion Criteria:
- Pre-existing peripheral neuropathy > grade 2 with pain (CTC version 4.0).
- Hematologic criteria: ANC < 500/uL, Platelets < 25,000 uL.
- Renal function: CrCl < 15 ml/min.
- Active infection requiring intravenous antibiotics
- Known Active hepatitis B or C
- SGOT (AST) and SGPT (ALT) > 3x institutional ULN
- Direct bilirubin > 1.5 mg/dL
- Patients must not have any severe and/or uncontrolled medical condition or other
conditions that could affect their participation in the study, including, but not
restricted to:
- Symptomatic congestive heart failure of New York Heart Association Class III or IV.
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 3 months of start of study treatment, serious uncontrolled cardiac arrhythmia
or any other clinically significant heart disease.
- Severely impaired lung function as defined as spirometry and DLCO (corrected for Hgb)
that is <50% of the normal predicted value and/or O2 saturation <88% at rest on room
air.
- Active (acute or chronic) or uncontrolled severe infections.

Additional Information

Waldenström's macroglobulinemia (WM) is a rare low-grade B-cell lymphoplasmacytic lymphoma.
Overall reported incidences approximately 3 cases per million persons per year with about
1500 and cases diagnosed annually in United States. There is a higher incidence in males
compared to females (3.4 vs 1.7 cases per 1 million person-years at risk) and WM is nearly
twice as common among whites compared to blacks.[1] A familial form of the disease is also
recognized. WM is an indolent disease with an overall median survival of 5 years although
more recent data suggest a disease-specific median survival of 11.2 years, given the
frequently older age (median 63 years) and accompanying co-morbidities at diagnosis(1). WM
is characterized by infiltration of lymphoplasmacytic cells and bone marrow and by serum
immunoglobulin M (IgM) monoclonal gammopathy. B-cell origin and some clinical cellular and
epidemiological features are shared among WM arises from intermediately mature B cells
(somatically mutated post germinal center the lymphocytes that have not yet undergone
isotype switching), as opposed to immature B cells from which chronic lymphocytic leukemia
arises in the fully mature, somatically mutated, from which cells multiple myeloma arises.
There is no standard of care for WM (2). Therefore, involving the patient's in clinical
trials is strongly recommended whenever possible.

Trial information was received from ClinicalTrials.gov and was last updated in August 2015.

Information provided to ClinicalTrials.gov by Hackensack University Medical Center.